Molecular interaction between K-Ras and H-REV107 in the Ras signaling pathway
Ras proteins are small GTPases that serve as master moderators of a large number of signaling pathways involved in various cellular processes. Activating mutations in Ras are found in about one-third of cancers. H-REV107, a K-Ras binding protein, plays an important role in determining K-Ras function. H-REV107 is a member of the HREV107 family of class II tumor suppressor genes and a growth inhibitory Ras target gene that suppresses cellular growth, differentiation, and apoptosis. Expression of H-REV107 was strongly reduced in about 50% of human carcinoma cell lines. However, the specific molecular mechanism by which H-REV107 inhibits Ras is still unknown. In the present study, we suggest that H-REV107 forms a strong complex with activating oncogenic mutation Q61H K-Ras from various biochemical binding assays and modeled structures. In addition, the interaction sites between K-Ras and H-REV107 were predicted based on homology modeling. Here, we found that some structure-based mutants of the K-Ras disrupted the complex formation with H-REV107. Finally, a novel molecular mechanism describing K-Ras and H-REV107 binding is suggested and insights into new K-Ras effector target drugs are provided. - Highlights: • H-REV107 interacts strongly with active GNP-bound K-Ras mutation. • H-REV107 rotated dramatically to interact with K-Ras Q61H (GNP) from the binding position with K-Ras WT (GDP). • In the K-Ras and H-REV107 interaction, E31 of K-Ras is an important binding residue. • H-REV107 can be a stable drug target for oncogenic K-Ras mutation.
- OSTI ID:
- 22719075
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 491, Issue 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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